This proposal is built upon the epidemiologic and molecular genetic findings from our 20-year experience in translational research in oral premalignant lesions (OPLs), a hallmark of oral cancer development. Although the etiology of OPLs is not fully understood, these lesions are often associated with tobacco and alcohol exposures; however, it is unclear why only a fraction of exposed individuals with OPL subsequently develop oral cancer. We have previously shown that OPL patients with certain genetic backgrounds are more susceptible to developing oral cancer, and that certain molecular abnormalities that present in OPL target tissues predict a higher rate of malignant transformation of these lesions, independent of clinicopathologic parameters. These predictive markers include OPL histology and the combined biomarker scores of chromosomal polysomy, p53 protein expression, and loss of heterozygosity (LOH) at 3p and 9p in OPL tissues. We have demonstrated a successful strategy for comprehensive cancer risk assessment in OPL patients by combining conventional medical/demographic variables and a panel of biomarkers; however, all of these studies have utilized small sample sizes. We propose to extend our studies by utilizing the largest available resource of OPL specimens that allows us the unprecedented opportunity to study 350 patients with OPLs, prospectively followed, to parallel our investigation of genetic markers in surrogate and target tissues, critical molecular candidates, and global genetic aberrations and expression profiles to identify predictors of oral cancer risk in these patients. Using this unique resource, we will integrate clinical, epidemiologic, and genetic data to build a quantitative risk assessment model for oral cancer development. Our Specific Aims include: 1) Assess susceptibility markers in surrogate tissue (lymphocytes); 2) Assess global genomic and transcriptomic abnormalities as well as critical candidate molecules in OPL target tissues; and 3) Complete comprehensive analyses of data from clinical, epidemiologic, surrogate-target tissue, genotype-phenotype, global-candidate biomarker panels with patients' clinical outcomes to build a risk assessment model for oral cancer development. The identification of subgroups of OPL patients at higher risk for oral cancer development will allow the development of individually tailored, mechanism-based chemopreventive interventions and strategies for more effective screening and treatment.